Journal Article

MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer

Mao, Mao, Ganini, Douglas, Consolaro, Marcia E. L., Bonini, Marcelo G., Ansenberger-Fricano, Kristine, Hart, Peter C., Santos, Janine H., de Abreu, Andre Luelsdorf P., Minshall, Richard D., Kajdacsy-Balla, Andre, Ekoue, Dede N., Diamond, Alan M.

2015

Overview

Manganese superoxide dismutase (MnSOD/SOD2) is a mitochondria-resident enzyme that governs the types of reactive oxygen species egressing from the organelle to affect cellular signalling. Here we demonstrate that MnSOD upregulation in cancer cells establishes a steady flow of H 2 O 2 originating from mitochondria that sustains AMP-activated kinase (AMPK) activation and the metabolic shift to glycolysis. Restricting MnSOD expression or inhibiting AMPK suppresses the metabolic switch and dampens the viability of transformed cells indicating that the MnSOD/AMPK axis is critical to support cancer cell bioenergetics. Recapitulating in vitro findings, clinical and epidemiologic analyses of MnSOD expression and AMPK activation indicated that the MnSOD/AMPK pathway is most active in advanced stage and aggressive breast cancer subtypes. Taken together, our results indicate that MnSOD serves as a biomarker of cancer progression and acts as critical regulator of tumour cell metabolism. Tumour cells sustain high levels of glycolysis even in presence of oxygen, which is known as the Warburg effect. Here the authors show that MnSOD contributes to the Warburg effect by increasing the levels of H 2 O 2 released from mitochondria, which sustains glycolysis by activating AMPK.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/31 / 13/89 / 13/95 / 14/1 / 14/10 / 14/19 / 14/34 / 14/63 / 631/337 / 631/443/319 / 631/67/1347 / 631/80/86 / AMP-Activated Protein Kinases - antagonists & inhibitors / AMP-Activated Protein Kinases - genetics / AMP-Activated Protein Kinases - metabolism / Bioenergetics / Breast Neoplasms - enzymology / Breast Neoplasms - genetics / Breast Neoplasms - pathology / Cell Line, Tumor / Colonic Neoplasms - enzymology / Colonic Neoplasms - genetics / Colonic Neoplasms - pathology / Female / Gene Expression Regulation, Neoplastic / Glycolysis - genetics / Hexokinase - genetics / Hexokinase - metabolism / Humanities and Social Sciences / Humans / Hydrogen Peroxide - metabolism / Male / Manganese / Mitochondria - enzymology / Mitochondria - genetics / multidisciplinary / Neoplasm Staging / Oxidation-Reduction / Phosphofructokinase-1 - genetics / Phosphofructokinase-1 - metabolism / Prostatic Neoplasms - enzymology / Prostatic Neoplasms - genetics / Prostatic Neoplasms - pathology / Pyruvate Kinase - genetics / Pyruvate Kinase - metabolism / Reactive Oxygen Species - metabolism / RNA, Small Interfering - genetics / RNA, Small Interfering - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Superoxide Dismutase - antagonists & inhibitors / Superoxide Dismutase - genetics / Superoxide Dismutase - metabolism / Transcriptional Activation